Jeff Kershaw

Activation detection in functional MRI using subspace modeling and maximum likelihood estimation

A statistical method for detecting activated pixels in functional MRI (fMRI) data is presented. In this method, the fMRI time series measured at each pixel is modeled as the sum of a response signal which arises due to the experimentally controlled activation-baseline pattern, a nuisance component representing effects of no interest, and Gaussian white noise. For periodic activation-baseline patterns, the response signal is modeled by a truncated Fourier series with a known fundamental frequency but unknown Fourier coefficients. The nuisance subspace is assumed to be unknown. A maximum likelihood estimate is derived for the component of the nuisance subspace which is orthogonal to the response signal subspace. An estimate for the order of the nuisance subspace is obtained from an information theoretic criterion. A statistical test is derived and shown to be the uniformly most powerful (UMP) test invariant to a group of transformations which are natural to the hypothesis testing problem. The maximal invariant statistic used in this test has an F distribution. The theoretical F distribution under the null hypothesis strongly concurred with the experimental frequency distribution obtained by performing null experiments in which the subjects did not perform any activation task. Applications of the theory to motor activation and visual stimulation fMRI studies are presented.

SPIO-PICsome: Development of a highly sensitive and stealth-capable MRI nano-agent for tumor detection using SPIO-loaded unilamellar polyion complex vesicles (PICsomes)

Size controllable polyion complex vesicles (PICsomes), composed of biocompatible poly(ethylene glycol) (PEG) and poly(amino acid)s, have an extremely prolonged lifetime in the bloodstream that enables them to accumulate effectively in tumors via the enhanced permeability and retention (EPR) effect. The purpose of this study was to use PICsomes to synthesize a highly sensitive MRI contrast agent for more precise tumor detection. We synthesized SPIO-Cy5-PICsomes (superparamagnetic iron oxide nanoparticle-loaded Cy5-cross-linked Nano-PICsomes) and characterized them using dynamic light scattering and transmission electron microscopy in vitro and evaluated their ability to detect subcutaneously grafted tumors in vivo with MRI. The transverse relaxivity (r2) of the SPIO-Cy5-PICsomes (r2=663±28mM(-1)s(-1)) was 2.54 times higher than that of bare clinically-used SPIO. In in vivo MRI experiments on mice subcutaneously grafted with colon-26 tumor cells, the tumor signal was significantly altered at 3h after SPIO-Cy5-PICsome administration and persisted for at least 24h. Small and early-stage in vivo tumors (3days after grafting, approximately 4mm(3)) were also clearly detected with MRI. SPIO-loaded PICsomes are sensitive MRI contrast agents that can act as a powerful nanocarrier to detect small tumors for early diagnosis.

In vivo visualization of reactive gliosis using manganese-enhanced magnetic resonance imaging

Reactive astrogliosis occurs after diverse central nervous system (CNS) insults. While astrogliosis provides protection against inflammation, it is also obstructive in the progress of neuranagenesis after CNS insults. Thus, a method that enables in vivo visualization and tissue characterization for gliosis would be invaluable for studies of CNS insults and corresponding treatments. Manganese has proven to be a useful MRI contrast agent that enters cells via Ca(2+) channels and has been applied to manganese-enhanced MRI (MEMRI) for neuronal functional mapping. This study investigated whether MEMRI can detect astrogliosis after focal ischemia in vivo. Rats were divided into groups according to the number of days after either transient middle cerebral artery occlusion or a sham. Ring- or crescent-shaped enhancement of MEMRI corresponded to the GFAP-positive astroglia observed in the peripheral region of the ischemic core 11 days after middle cerebral artery occlusion. This indicates that MEMRI enhancement predominantly reflects reactive astrogliosis after stroke.

Systematic changes to the apparent diffusion tensor of in vivo rat brain measured with an oscillating-gradient spin-echo sequence

As the oscillating gradient spin-echo sequence has shown promise as a means to probe tissue microstructure, it was applied here to diffusion-tensor imaging of in vivo rat brain. The apparent diffusion tensor (ADT) was estimated for motion-probing gradient (MPG) frequencies in the range 33.3-133.3 Hz, and regions-of-interest (ROIs) in the corpus callosum (CC), visual cortex (VC), cerebellar white matter (CBWM) and cerebellar grey matter (CBGM) were selected for detailed analysis. There were substantial, approximately linear changes to the ADT with increasing MPG frequency for all four ROIs. All ROIs showed clear increases in mean diffusivity. CBWM had a substantial decrease in fractional anisotropy, whereas the CC and VC had minor increases of the same parameter. All eigenvalues of the ADT tended to increase with frequency for the CBWM, CBGM and VC, but only the principal eigenvalue increased strongly for the CC. On the other hand, there was no evidence that the orientation of the principal eigenvector varied systematically with MPG frequency for any of the ROIs. The relationship between the behaviour of the eigenvalues and the behaviours of the mean diffusivity and fractional anisotropy is investigated in detail. Pixelwise linear fits to the MD from individual animals found elevated changes across the cerebellum. The data acquired for this work encompassed a range of effective diffusion-times from 7.5 ms down to 1.875 ms, and some ideas on how the results might be used to extract quantitative information about brain tissue microstructure are discussed.

Confirming the existence of five peaks in 129Xe rat head spectra

A series of experiments were performed to investigate why two peaks (D and E) of the five dissolved phase peaks in hyperpolarized 129Xe rat head spectra appeared inconsistently in previous work. Specifically, spectra were acquired under conditions of various shim states, anaesthetics, and arterial ligation. The shimming experiments showed that slice‐shimming can be used to improve resolution of the dissolved phase peaks, but even so, subtle changes in the shim state that may dramatically alter the shape of peak E remain poorly understood. Also, the inability to shim gas spaces and tissue simultaneously may explain why inconsistent chemical shift values have been reported in the literature. A possible solution for this problem is suggested. The results of pre‐ and postligation spectra from the same animal indicated that two peaks (A and E) originate from brain. Changing the anaesthetic was found to have no effect on the number of dissolved peaks in xenon spectra. Magn Reson Med 57:791–797, 2007.

Nonlinear correlation between field potential and local cerebral blood flow in rat somatosensory cortex evoked by changing the stimulus current

The relationship between local cerebral blood flow (LCBF) and field potential (FP) evoked by hindpaw stimulation in rat somatosensory cortex has been investigated while changing stimulus current. The change in LCBF was measured using laser-Doppler flowmetry and the field potential was acquired using a tungsten electrode inserted into the cortex of alpha-chloralose-anesthetized rats. The cortex was activated by electrical stimulation of the hind paw with 5 Hz pulses (0.1 ms) applied at currents of 1.0, 1.5, 2.0 and 2.5 mA for 5 s. It was found that the summed FP is nonlinear with respect to stimulus current, whereas the integrated LCBF response is linear across the range of currents used in the experiment. This means that the relationship between the summed FP and integrated LCBF is nonlinear as a function of stimulus current.

129Xe spectra from the heads of rats with and without ligation of the external carotid and pterygopalatine arteries.

After rats inhaled hyperpolarized 129Xe gas, in vivo spectra from their heads revealed a dominant peak around 195 ppm, another easily resolvable peak near 189 ppm, a broad peak around 210 ppm, and two minor peaks around 198 ppm and 192 ppm. However, the source of each peak remains controversial. To further study the origin of each peak, we compared spectra obtained from the heads of normal rats with spectra taken from the heads of rats that had undergone ligation of the external carotid (ECA) and pterygopalatine (PPA) arteries, the major feeding vessels of nonbrain tissue in the rat head. The amplitude of the peak at around 189 ppm was greatly reduced in the ECA/PPA‐ligated rats, while the peak around 195 ppm persisted. We conclude that the signal that originates from the rat brain after inhalation of 129Xe gas is overwhelmingly dominated by the single resonance at 195 ppm. Magn Reson Med 53:528–534, 2005.

Hyperoxia modified activation-induced blood oxygenation level-dependent response of human visual cortex (V1): an event-related functional magnetic resonance imaging study

To investigate the effect that hyperoxia has on the blood oxygenation level-dependent (BOLD) response to visual stimulation of human V1, an event-related functional magnetic resonance imaging technique was applied. The event-related paradigm consisted of 2 s of stimulation by a checkerboard reversing at a frequency of 8 Hz, followed by 18 s of control scans. The peak height and peak time of the BOLD response curves were compared under normoxic and hyperoxic conditions. It was found that the peak height was larger and the peak time shorter for hyperoxia than for normoxia. These results suggest that hyperoxia modified the activation-induced hemodynamic response of human V1.

Hyperoxia-enhanced activation-induced hemodynamic response in human VI: an fMRI study.

The effect hyperoxia had on the hemodynamic response to visual stimulation (black and white checkerboard alternating at a frequency of 8 Hz) of human VI was investigated using a blood oxygenation level-dependent (BOLD) contrast with an fMRI technique. Data were acquired with a 5 on/5 off block paradigm using single-shot gradient-echo echo-planar imaging. Using a two-tailed paired t-test (p < 0.05, n = 13) it was found that the mean percentage signal change and the mean number of activated pixels was significantly increased for hyperoxia (5.7 ± 0.9, 187 ± 73, mean ± SD) relative to those for normoxia (5.4 ± 0.9, 168 ± 58). We believe that these results indicate that hyperoxia enhances the activation-induced hemodynamic response in human VI.

High b-value diffusion-weighted fMRI in a rat forepaw electrostimulation model at 7 T.

Spin-echo diffusion-weighted functional MRI (DW-fMRI) was performed on a rat forepaw electrostimulation model at 7 T. This small animal model used electric (rather than visual) stimulation and allowed DW-fMRI experiments to be performed over a broader range of acquisition parameters than previous work on humans and cats. Resting state experiments with injections of ultra-small superparamagnetic iron oxide (USPIO) were also used to investigate the effects of gradient coupling on the signal change. The experiments were performed over five b-values (0, 200, 800, 1400 and 2000s/mm(2)) and three echo-times (30, 60 and 90 ms). Alterations to the stimulation-induced response with respect to TE and b-value were evaluated in two intervals: the positive stimulus-correlated response (5-20s after stimulus onset) and the post-stimulus undershoot (27-40s). There was no strong dependence of the signal change on b-value for any of the intervals or TEs. Similarly, changes to the apparent transverse relaxation rate showed no clear dependence on b-value. In contrast to previous DW-fMRI studies, the simplest explanation for the observed data is a single-compartment signal model with the functional signal changes probably corresponding to extravascular SE-BOLD. Experiments with USPIO suggested that at 7 T and within the range of parameters used, the influence of gradient coupling may be sufficient to explain minor DW-fMRI signal changes.